This application, Cellular regulation of the IL-22 receptor and its importance in lung immunity, is submitted by me, Dr. Nathaniel Weathington, MD PhD in the University of Pittsburgh Department of Medicine, Division of Pulmonary Allergy, and Critical Care Medicine for a mentored Career Development Award (K08). I have a strong background and commitment to research in pulmonary inflammation biology with aspirations to ultimately direct a center on lung inflammation biology. I propose a research-intensive period of career development with hands-on and didactic training integrated into the activities planned. To complete my primary research Aims, I will gain and extend expertise in protein chemistry, cell biologic, and animal model techniques. I present preliminary data on modulation of the interleukin (IL)-22 signaling axis, which is essential and protective for Type 17 immune responses. Molecular regulation of IL-22 receptor (IL-22R) protein levels is unknown, and I show that IL-22R is degraded by the ubiquitin (Ub) proteasome with identification of a molecular motif for IL-22R ubiquitination. I also observe that the uncharacterized Ub E3 ligase subunit FBXW22 shuttles the IL-22R protein for degradation in lung epithelial cells. Further, the multi-functional kinase glycogen synthase kinase 3? phosphorylates and stabilizes IL-22R in cells. Based on this, I propose to more specifically characterize IL-22R regulation, study abundance of involved proteins in human specimens for disease correlation, and test the hypothesis that stabilization of IL-22R in vivo can protect from pneumonia. My work will proceed under close advisement from my primary mentor and research advisors. I also propose select coursework for enrichment on translational science and personalized medicine. I have an environment of enduring support at the University of Pittsburgh from my advisors, mentor, division, and department, and will be promoted to Assistant Professor of Medicine on completion of my fellowship in summer 2014. With support from the K08 mentored Career Development Award, this project will yield publications and presentations, and I will develop my research to an independent project with a transition to independence and application for an R01 project award in the next five years.